Compound for inhibiting and degrading tyrosine protein kinase ALK

ABSTRACT

Provided is a compound for inhibiting and degrading anaplastic lymphoma kinase ALK. Specifically provided is a compound as represented by the following formula I, wherein the definition of each group is as stated in the description. The compound has excellent anaplastic lymphoma kinase (ALK) inhibitory activity, and can be used for preparing drugs for treatment of ALK activity-related diseases.

TECHNICAL FIELD

The present invention belongs to the field of medicine, and particularlyrelates to a class of compounds inhibiting and degrading tyrosineprotein kinase ALK, the preparation thereof and the application thereof.

BACKGROUND

Anaplastic lymphoma kinase (ALK) is a receptor-type protein tyrosinephosphokinase. It can accept extracellular signals and regulate cellgrowth, differentiation, survival and transformation. Structurally, ALKincludes an extracellular ligand-binding region, a transmembrane region,and an intracellular domain.

Initially, ALK was discovered as an activated fusion oncogene inanaplastic large cell lymphoma and in subsequent studies fusion forms ofALK have been found in a variety of cancers, including systemic tissuedysplasia, inflammatory myofibroblastoma, non-small cell lung cancer,etc. The ALK mutation and its abnormal activities in a variety ofcancers have made ALK a drug target for treating ALK-positive cancers.

The forms of ALK mutations have phenomenons such as overexpression,formation of fusion genes with other genes, and point mutations. ALKgene fusion mutation is a common driver gene in non-small cell lungcancer (NSCLC). The percentage of ALK fusion mutations positive inChinese non-small cell lung adenocarcinoma is 5.3%, and it has higherincidence in younger patients (younger than 60 years) with non-smallcell lung adenocarcinoma and non-smokers. ALK-positive non-small celllung cancer is considered as a molecular subtype, and the correspondingtargeting drug is completely different from the EGFR molecular subtype.A number of drugs as an ALK inhibitor (eg, crizotinib, erlotinib,ceritinib) have been marketed for the treatment of non-small cell lungcancer.

Therefore, those skilled in the art are dedicated to developingcompounds capable of inhibiting the tyrosine protein kinase ALKactivity.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a compound capable ofinhibiting and degrading tyrosine protein kinase ALK, the preparationthereof and the application thereof.

In the first aspect of the present invention, there is provided acompound represented by the following formula I, or a pharmaceuticallyacceptable salt thereof:

wherein,

— refers to a single bond;

refers to a single or double bond;

A is missing or selected from C(═O), C(═O)X1, (CR₃₅R₃₆)_(k)C(═O)X1,SOX1, SO₂X1, C₁₋₈ hydrocarbyl group with or without substituent(s), C₁₋₈cyclic hydrocarbyl group with or without substituent(s), and C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s); whereinX1 is missing or selected from (CR₃₅R₃₆)_(k)O, (CR₃₅R₃₆)_(k)S and NR₁₄;wherein R₃₅, R₃₆, R₁₄ is each independently selected from H, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s) and C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s); k is an integerbetween 0 and 3;

W is missing or selected from O, NR₁₇, —X2C(═O)X3, and —X2S(═O)_(g)X3;wherein R₁₇ is H, C₁₋₈ hydrocarbyl group with or without substituent(s),C₁₋₈ cyclic hydrocarbyl group with or without substituent(s), or C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s); whereinX2, X3 is each independently missing or selected from O, S, and NR₁₈;wherein g is an integer between 0 and 2; wherein R₁₈ is H, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), or C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s);

Y is (CR₂₂R₂₃)_(h), CHX4(CR₂₂R₂₃)_(h), CX4=CH(CR₂₂R₂₃)_(h), or(CR₂₂R₂₃)_(h); wherein h is an integer between 0 and 30; wherein R₂₂,R₂₃ is each independently selected from H, cyano, hydroxyl, amino, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s), and C₁₋₈hydrocarbyloxy group with or without substituent(s); wherein X4 is H,halogen, cyano, nitro, hydroxyl, C₁₋₈ hydrocarbyloxy group with orwithout substituent(s), C₁₋₈ hydrocarbyloxycarbonyl group with orwithout substituent(s), C₁₋₈ amino group with or without substituent(s),C₁₋₈ ester group with or without substituent(s), C₁₋₈ aminocarbonylgroup with or without substituent(s), C₁₋₈ hydrocarbyl group with orwithout substituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), or C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s);

Z is (CR₂₄R₂₅)_(i), CHX5(CR₂₄R₂₅)_(i), CX5=CH(CR₂₄R₂₅)_(i) orC≡C(CR₂₄R₂₅)_(i); wherein i is an integer between 0 and 30; wherein R₂₄,R₂₅ is each independently selected from H, cyano, hydroxyl, amino, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s), and C₁₋₈hydrocarbyloxy group with or without substituent(s); wherein X5 is H,halogen, cyano, nitro, hydroxyl, C₁₋₈ hydrocarbyloxy group with orwithout substituent(s), C₁₋₈ hydrocarbyloxycarbonyl group with orwithout substituent(s), C₁₋₈ amino group with or without substituent(s),C₁₋₈ ester group with or without substituent(s), C₁₋₈ aminocarbonylgroup with or without substituent(s), C₁₋₈ hydrocarbyl group with orwithout substituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), or C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s);

B is missing or selected from O, C═O, S, NR₁₅, —NR₁₅C(═O)—, —C(═O)NR₁₅—,—C(═O)O—, OC(═O)O—, —NR₁₅C(═O)O—, —OC(═O)NR₁₅—, —NR₁₅C(═O)NR₁₆—, C₁₋₁₂hydrocarbyl group with or without substituent(s), C₁₋₁₂ cyclichydrocarbyl group with or without substituent(s), and C₁₋₁₂ heterocyclichydrocarbyl group with or without substituent(s); wherein R₁₅, R₁₆ iseach independently selected from H, C₁₋₈ hydrocarbyl group with orwithout substituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), and C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s);

X is selected from CR₁₉R₂₀, C(═O), S(═O), SO₂, and NR₂₁; wherein R₁₉,R₂₀ is each independently selected from H, cyano, hydroxyl, amino, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s), and C₁₋₈hydrocarbyloxy group with or without substituent(s); wherein R₂₁ isselected from H, C₁₋₈ hydrocarbyl group with or without substituent(s),C₁₋₈ cyclic hydrocarbyl group with or without substituent(s), and C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s);

R₁, R₈, R₁₁ is each independently selected from H, C₁₋₈ hydrocarbylgroup with or without substituent(s), C₁₋₈ cyclic hydrocarbyl group withor without substituent(s), C₁₋₈ heterocyclic hydrocarbyl group with orwithout substituent(s) and C₁₋₆ acyl group with or withoutsubstituent(s);

R₂, R₅ is each independently selected from hydrogen, OR₂₆, NR₂₇R₂₈,cyano, halogen, C₁₋₈ hydrocarbyl group with or without substituent(s),C₁₋₈ cyclic hydrocarbyl group with or without substituent(s), C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s), C₁₋₆ acylgroup with or without substituent(s) and C₁₋₆ amido group with orwithout substituent(s); wherein R₂₆, R₂₇, R₂₈ is each independentlyselected from II, C₁₋₈ hydrocarbyl group with or without substituent(s),C₁₋₈ cyclic hydrocarbyl group with or without substituent(s), and C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s);

R₃, R₆, R₇, R₉, R₁₀, R₁₂, R₁₃ is each independently selected from H,OR₂₉, NR₃₀R₃₁, cyano, halogen, nitro, C₁₋₈ hydrocarbyl group with orwithout substituent(s), cyclic hydrocarbyl group with or withoutsubstituent(s), heterocyclic hydrocarbyl group with or withoutsubstituent(s), X6S(═O)_(j)R₃₂, and X6C(═O)R₃₃; wherein j is an integerbetween 0 to 2; wherein R₂₉, R₃₀, R₃₁, R₃₂, R₃₃ is each independentlyselected from H, C₁₋₈ hydrocarbyl group with or without substituent(s),C₁₋₈ cyclic hydrocarbyl group with or without substituent(s) and C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s); whereinX6 is missing or selected from O, S, and NR₃₄; wherein R₃₄ is H, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), or C_(1_8)heterocyclic hydrocarbyl group with or without substituent(s);

R₄ is selected from H, cyano, carboxyl, C₁₋₈ hydrocarbyl group with orwithout substituent(s), and C₁₋₈ hydrocarbyloxycarbonyl group with orwithout substituent(s);

a is an integer between 0 and 5 (such as 1, 2, 3, 4, 5);

b is an integer between 0 and 3 (such as 1, 2, 3);

c is an integer between 0 and 30 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9);

d is an integer between 0 and 9 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9);

e is an integer between 0 and 3 (such as 1, 2, 3);

f is an integer between 0 and 4 (such as 1, 2, 3, 4).

In another preferred example, A is missing; W is —X2C(═O)X3, wherein X3is NR¹⁸ and X2 is missing, or X2 is NR₁₈ and X3 is missing; Y is(CR₂₂R₂₃)_(h), wherein R₂₂, R₂₃ is each independently selected from H,hydroxyl, and C₁₋₄ hydrocarbyl group with or without substituent(s), his an integer between 1 and 6; Z is (CR₂₄R₂₅)_(i), wherein R₂₄, R₂₅ iseach independently selected from H, hydroxyl, and C₁₋₄ hydrocarbyl groupwith or without substituent(s), i is an integer between 1 and 6; c is 0.

In another preferred example, A is missing; W is missing or O; Y is(CR₂₂R₂₃)_(h), wherein R₂₂, R₂₃ is each independently selected from II,hydroxyl, and C₁₋₄ hydrocarbyl group with or without substituent(s), his an integer between 0 and 3; B is O; Z is (CR₂₄R₂₅),, wherein R₂₄, R₂₅is each independently selected from H, hydroxyl, and C₁₋₄ hydrocarbylgroup with or without substituent(s), i is an integer between 0 and 3; cis an integer between 1 and 6.

In another preferred example, A is C(═O)X1; wherein X1 is missing orselected from (CR₃₅R₃₆)_(k)O and (CR₃₅R₃₆)_(k)S, wherein k is an integerbetween 0 and 2; R₃₅, R₃₆ is each independently II, or C₁₋₄ alkyl; W isNR₁₇, wherein R₁₇ is II, or C₁₋₄ hydrocarbyl group with or withoutsubstituent(s); Y is (CR₂₂R₂₃)_(h), wherein R₂₄, R₂₅ is eachindependently selected from H, hydroxyl, and C₁₋₄ hydrocarbyl group withor without substituent(s), h is an integer between 0 and 3; Z is(CR₂₄R₂₅)_(i), wherein R₂₄, R₂₅ is each independently selected from H,hydroxyl, C₁₋₄ hydrocarbyl group with or without substituent(s), i is aninteger between 0 and 3; B is 0; c is an integer between 1 and 4.

In another preferred example, A is SO₂X1; wherein X1 is missing orselected from O and S; W is O; Y is (CR₂₂R₂₃)_(h), wherein R₂₂, R₂₃ iseach independently selected from H, hydroxyl, and C₁₋₄ hydrocarbyl groupwith or without substituent(s), h is an integer between 1 and 6; Z is(CR₂₄R₂₅)_(i), wherein R₂₄, R₂₅ is each independently selected from H,hydroxyl, and C₁₋₄ hydrocarbyl group with or without substituent(s), iis an integer between 0 and 3; c is 0.

In another preferred example, A is missing; W is NR₁₇; wherein R₁₇ is H,or C₁₋₄ hydrocarbyl group with or without substituent(s); Y is(CR₂₂R₂₃)_(h), wherein R_(n), R₂₃ is each independently selected fromII, hydroxyl, and C₁₋₄ hydrocarbyl group with or without substituent(s),h is an integer between 0 and 3; Z is (CR₂₄R₂₅)_(h), wherein R₂₄, R₂₅ iseach independently selected from II, hydroxyl, and C₁₋₄ hydrocarbylgroup with or without substituent(s), i is an integer between 0 and 4; Bis O; c is an integer between 1 and 6.

In another preferred example, A is missing; W is missing; Y is(CR₂₂R₂₃)₁₁, wherein R₂₂, R₂₃ is each independently selected from H,hydroxyl, and C₁₋₄ hydrocarbyl group with or without substituent(s), his an integer between 0 and 3; Z is (CR₂₄R₂₅)_(i), wherein R₂₄, R₂₅ iseach independently selected from FI, hydroxyl, and C₁₋₄ hydrocarbylgroup with or without substituent(s), i is an integer between 0 and 3; Bis O; c is an integer between 1 and 10.

In another preferred example, A is (CH₂)_(k)C(—O)X1; wherein X1 ismissing or —NH—; k is an integer between 1 and 3.

In another preferred example, any of the substituents is selected fromthe group consisting of halogen, unsubstituted or halogenated C1-C6alkyl, unsubstituted or halogenated C1-C6 alkoxy, unsubstituted orhalogenated C2-C6 alkoxyalkyl, unsubstituted or halogenated C3-C8cycloalkyl, unsubstituted or halogenated C2-C6 alkylcarbonyl,unsubstituted or halogenated C1-C6 alkylene-hydroxyl, unsubstituted orC1-C6 alkyl substituted amine.

In another preferred example, the structure of the compound isrepresented by formula I′:

wherein, each group is defined as described above.

In another preferred example, the structure of the compound isrepresented by formula I″:

wherein, each group is defined as described above.

In another preferred example, in formula I, F, r, or I′″,

refers to a single bond.

In another preferred example, X is C(═O).

In another preferred example, R₁, R₈, R₁₁ is each independently selectedfrom H and C₁₋₄ alkyl with or without substituent(s).

In another preferred example, R₂, R₅ is each independently selected fromH and C₁₋₄ alkyl with or without substituent(s).

In another preferred example, R₃ is selected from H and C₁₋₄ alkyl withor without substituent(s).

In another preferred example, R₆ is selected from II, C₁₋₄ alkyl with orwithout substituent(s), and OR₂₉; wherein R₂₉ is selected from H andC₁₋₆ alkyl with or without substituent(s).

In another preferred example, R₇ is selected from H and C₁₋₄ alkyl withor without substituent(s).

In another preferred example, R₉ is selected from H and C₁₋₄ alkyl withor without substituent(s).

In another preferred example, R₁₀ is selected from halogen, cyano,nitro, and C₁₋₄ alkyl with or without substituent(s).

In another preferred example, R₁₂ is selected from hydrogen, halogen,cyano, nitro, and X6S(═O)_(j)R₃₂; wherein X6 is missing and R₃₂ isselected from H and C₁₋₆ alkyl with or without substituent(s).

In another preferred example, R₄ is selected from H, cyano and C₁₋₆alkyl with or without substituent(s).

In another preferred example, R₁₂ is X6S(═O)_(j)R₃₂; wherein X6 ismissing, j is 2 and R₃₂ is C₁₋₃ alkyl (preferably isopropyl) with orwithout substituent(s).

In the second aspect of the present invention, there is provided apharmaceutical composition, which comprises the compound according tothe first aspect or a pharmaceutically acceptable salt thereof, or aprodrug thereof, and a pharmaceutically acceptable carrier.

In another preferred example, the effective amount refers to atherapeutically effective amount or an inhibitory effective amount,preferably 0.01 to 99.99%.

In another preferred example, the pharmaceutical composition furthercomprises one or more other antitumor agents.

In another preferred example, the pharmaceutical composition is used toinhibit the activity of anaplastic lymphoma kinase (ALK).

In another preferred example, the pharmaceutical composition is used fortreating diseases related to the activity or expression level ofanaplastic lymphoma kinase (ALK).

In the third aspect of the present invention, there is provided a use ofthe compound according to the first aspect of the present invention for:

(a) preparation of drugs for the treatment of diseases related to theactivity or expression level of anaplastic lymphoma kinase (ALK);

(b) preparation of anaplastic lymphoma kinase (ALK) targeted inhibitorsor degradation agents;

(c) non-therapeutic inhibition or degradation of anaplastic lymphomakinase (ALK) in vitro;

(d) non-therapeutic inhibition of tumor cell proliferation in vitro;and/or

(e) treatment of diseases related to the activity or expression level ofanaplastic lymphoma kinase (ALK).

In another preferred example, the disease includes a tumor, andpreferably, the tumor includes non-small cell lung cancer, inflammatorymyofibroblastoma, and the like.

In the forth aspect of the present invention, there is provided a methodfor preparing the compound of formula I according to the first aspect ofthe present invention, comprising the steps of:

(a) reacting a compound of formula IV and a compound of formula II in aninert solvent to obtain a compound of formula I;

wherein, each group is defined as described above.

In another preferred example, the method further comprises the step of:

(a) reacting a compound of formula III and a compound of formula V in aninert solvent to obtain a compound of formula I.

In the fifth aspect of the present invention, there is provided a methodfor inhibiting or degrading anaplastic lymphoma kinase (ALK), comprisingthe step of administering an inhibitory effective amount of the compoundof formula I according to the first aspect of the present invention or apharmaceutically acceptable salt thereof to an inhibitory subject, oradministering an inhibitory effective amount of the pharmaceuticalcomposition according to the fourth aspect of the present invention toan inhibitory subject.

In another preferred example, the inhibition is non-therapeuticinhibition in vitro.

In another preferred example, when an inhibitory effective amount of thecompound of formula I according to claim 1 or a pharmaceuticallyacceptable salt thereof is administered to an inhibitory subject, theinhibitory effective amount is 0.001-500 nmol/L, preferably 0.01-200nmol/L.

In the sixth aspect of the present invention, there is provided a methodfor treating a disease related to the activity or expression level ofanaplastic lymphoma kinase (ALK), comprising a step of: administering atherapeutically effective amount of the compound of formula I accordingto the first aspect of the present invention or the pharmaceuticalcomposition according to the fourth aspect of the present invention to asubject in need of treatment.

In another preferred example, the subject is a mammal; preferably, themammal is a human.

In another preferred example, the disease related to the activity orexpression level of anaplastic lymphoma kinase (ALK) is a tumor,preferably the tumor is selected from the group consisting of non-smallcell lung cancer.

In the seventh aspect of the present invention, there is provided amethod for inhibiting tumor cells in vitro, comprising: administering aninhibitory effective amount of the compound of formula I according tothe first aspect of the present invention or the pharmaceuticalcomposition according to the second aspect of the present invention toan inhibitory subject.

It is to be understood that within the scope of the present invention,the various technical features of the present invention and the varioustechnical features specifically described hereinafter (as in theembodiments) may be combined with each other to form a new or preferredtechnical solution. Due to space limitations, we will not repeat themhere.

DETAILED DESCRIPTION OF THE INVENTION

After extensive and intensive research, the present inventors haveprepared a class of compounds having the structure as shown in formula Iand found that they have inhibitory and degradation activities toanaplastic lymphoma kinase (ALK). In addition, the compound has aninhibitory effect on anaplastic lymphoma kinase (ALK) at a very lowconcentration, and the inhibitory activity is quite excellent, so it canbe used for the treatment of diseases related to the activity orexpression level of anaplastic lymphoma kinase (ALK), such as tumors.The present invention has been completed on this basis.

The present invention discloses a new class of compounds and their usefor inhibiting and degrading tyrosine protein kinase (ALK). Thesecompounds can inhibit and degrade ALK and be used to treat non-smallcell lung cancer.

Term

In the present invention, the term “C₁₋₈ hydrocarbyl group” refers to afunctional group containing only two kinds of atoms of carbon andhydrogen, in which the number of carbon atoms is 1 to 8. A hydrocarbylgroup can be regarded as a free radical left after the correspondinghydrocarbon loses one hydrogen atom, which may be an alkyl group, acycloalkyl group, an alkenyl group, an alkynyl group, etc.; itsstructure may be linear, branched, or cyclic; and it may be aliphatic oraromatic. The term “C₁₋₆ alkyl” refers to a straight or branched alkylgroup having 1 to 6 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

The term “alkoxy” as used herein includes O-alkyl, in which “alkyl” isas defined above.

The term “halo” as used herein, unless otherwise indicated, includesfluoro, chloro, bromo or iodo.

The compound of the present invention may contain a double bond. Whensuch double bond is contained, the compound of the present inventionexists in cis form, trans form or mixtures thereof.

The halogens described herein include fluorine, chlorine, bromine andiodine.

Unless otherwise indicated, the alkyl and alkyl moieties of the alkoxygroup described herein may be linear, branched, or cyclic.

In the present invention, the term “cyclic hydrocarbyl group” refers toa functional group containing two kinds of atoms of carbon and hydrogen,and includes cycloalkyl, cycloalkenyl (containing at least onecarbon-carbon double bond), and aryl. They may be monocyclic, bicyclicor polycyclic. They may be Spiro rings or fused rings.

In the present invention, the term “heterocyclic hydrocarbyl group”refers to a functional group containing carbon, hydrogen, and at leastone heteroatom other than carbon and hydrogen. It includesheterocycloalkyl, heterocycloalkenyl (containing at least onecarbon-carbon double bond), and heteroaryl. One or more ring-formingatoms in the ring are heteroatoms. The heteroatom can be O, N, S, or anycombination thereof. They may be monocyclic, bicyclic or polycyclic.They may be Spiro rings or fused rings.

In the present invention, the term “substituent” includes, but is notlimited to, fluorine, chlorine, bromine, cyano, hydroxyl, amino, C₁₋₆hydrocarbyloxy group, C₁₋₆ halohydrocarbyl group, C₁₋₆ acyl group, andC₁₋₆ sulfonyl group.

The term “hydrocarbyloxy group” as used herein refers to anO-hydrocarbyl group, where the “hydrocarbyl group” is as defined above.

The term “hydrocarbyloxycarbonyl group” as used herein refers to aC(═O)O-hydrocarbyl group, in which the “hydrocarbyl group” is as definedabove.

The term “amino group” as used herein refers to N(H or hydrocarbylgroup 1) (H or hydrocarbyl group 2), in which the “hydrocarbyl group” isas defined above.

The term “aminocarbonyl group” as used herein refers to a C(═O)-aminogroup, in which the “amino group” is as defined above.

The term “amido group” as used herein refers to N(H or hydrocarbylgroup)-C(═O)-hydrocarbyl group, in which the “hydrocarbyl group” is asdefined above . . .

In the present invention, the term “containing”, “comprising” or“including” means that various ingredients can be used together in themixture or composition of the present invention. Thus, the terms“consisting essentially of and” consisting of are included in the term“containing”.

In the present invention, the term “pharmaceutically acceptable”ingredient refers to a substance suitable for human and/or animalswithout excessive adverse side effects (such as toxicity, irritation andallergy), which means it has a reasonable benefit/risk ratio.

In the present invention, the term “effective amount” refers to anamount of a therapeutic agent to treat, alleviate or prevent a targetdisease or condition, or an amount that exhibits a detectabletherapeutic or preventive effect. The exact effective amount for acertain subject will depend on the subject's size and health, the natureand extent of the condition, and the therapeutic agent and/orcombination of therapeutic agents chosen for administration. Therefore,it is not useful to specify an accurate effective amount in advance.However, for a given condition, routine experimentation can be used todetermine the effective amount, which can be determined by theclinician.

As used herein, unless specifically stated, the term “substituted”refers to the replacement of one or more hydrogen atoms on a group withsubstituent(s) selected from the group consisting of: halogen,unsubstituted or halogenated C₁₋₆ alkyl, unsubstituted or halogenatedC₂₋₆ acyl, unsubstituted or halogenated C₁₋₆ alkyl-hydroxy.

Unless otherwise specified, all compounds present in the presentinvention are intended to include all possible optical isomers, such asa single chiral compound, or a mixture of various chiral compounds(i.e., a racemate). Among all the compounds of the present invention,each chiral carbon atom may optionally be in the R configuration or theS configuration, or a mixture of the R configuration and the Sconfiguration.

As used herein, the term “compound of the present invention” refers to acompound of formula I. The term also includes various crystalline forms,pharmaceutically acceptable salts, hydrates or solvates of the compoundsof formula I.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt of a compound of the present invention with an acid or a basesuitable for use as a drug. The pharmaceutically acceptable saltsinclude inorganic and organic salts. One preferred kind of salt is asalt of a compound of the present invention with an acid. Suitable acidsfor forming salts include, but are not limited to, inorganic acids suchas hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuricacid, nitric acid, phosphoric acid, etc., organic acids such as formicacid, acetic acid, propionic acid, oxalic acid, malonic acid, succinicacid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, picric acid, methanesulfonic acid, benzylsulfonic acid,benzenesulfonic acid, etc.; and acidic amino acids such as asparticacid, glutamic acid, etc.

Compounds and Pharmaceutically Acceptable Salts Thereof

The present invention relates to a compound of formula I shown as belowor a pharmaceutically acceptable salt thereof;

wherein,

— refers to a single bond;

refers to a single or double bond; A is missing or selected from C(═O),C(═O)X1-, SOX1-, SO₂X1-, C₁₋₈ hydrocarbyl group with or withoutsubstituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), and C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s); wherein X1 is missing or selected from (CR₃₅R₃₆)_(k)O,(CR₃₅R₃₆)_(k)S and NR₁₄; wherein R₃₅, R₃₆, R₁₄ is each independentlyselected from H, C₁₋₈ hydrocarbyl group with or without substituent(s),C₁₋₈ cyclic hydrocarbyl group with or without substituent(s), and C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s); k is aninteger between 0 and 3;

W is missing or selected from O, NR₁₇, —X2C(═O)X3, and —X2S(═O)_(g)X3;wherein R₁₇ is H, C₁₋₈ hydrocarbyl group with or without substituent(s),C₁₋₈ cyclic hydrocarbyl group with or without substituent(s), or C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s); whereinX2, X3 is each independently missing or selected from O, S, and NR₁₈;wherein g is an integer between 0 and 2; wherein R₁₈ is H, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), or C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s);

Y is (CR₂₂R₂₃)_(h), CHX4(CR₂₂R₂₃)_(h), CX4-CH(CR₂₂R₂₃)_(h), or(CR₂₂R₂₃)_(h); wherein h is an integer between 0 and 30; wherein R₂₂,R₂₃ is each independently selected from H, cyano, hydroxyl, amino, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s), and C₁₋₈hydrocarbyloxy group with or without substituent(s); wherein X4 is H,halogen, cyano, nitro, hydroxyl, C_(i)s hydrocarbyloxy group with orwithout substituent(s), C₁₋₈ hydrocarbyloxycarbonyl group with orwithout substituent(s), C₁₋₈ amino group with or without substituent(s),C₁₋₈ ester group with or without substituent(s), C₁₋₈ aminocarbonylgroup with or without substituent(s), C₁₋₈ hydrocarbyl group with orwithout substituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), or C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s);

Z is (CR₂₄R₂₅)_(i), CHX5(CR₂₄R₂₅)_(i), CX5-CH(CR₂₄R₂₅), or C═C(CR₂₄R₂₅);wherein i is an integer between 0 and 30; wherein R₂₄, R₂₅ is eachindependently selected from H, cyano, hydroxyl, amino, C₁₋₈ hydrocarbylgroup with or without substituent(s), C₁₋₈ cyclic hydrocarbyl group withor without substituent(s), C₁₋₈ heterocyclic hydrocarbyl group with orwithout substituent(s), and C₁₋₈ hydrocarbyloxy group with or withoutsubstituent(s); wherein X5 is H, halogen, cyano, nitro, hydroxyl, C₁₋₈hydrocarbyloxy group with or without substituent(s), C₁₋₈hydrocarbyloxycarbonyl group with or without substituent(s), C₁₋₈ aminogroup with or without substituent(s), C₁₋₈ ester group with or withoutsubstituent(s), C₁₋₈ aminocarbonyl group with or without substituent(s),C₁₋₈ hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), or C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s);

B is missing or selected from O, C═O, S, NR₁₅, —NR₁₅C(═O)—, —C(═O)NR₁₅—,—C(═O)O—, OC(═O)O—, —NR₁₅C(═O)O—, —OC(═O)NR₁₅—, —NR₁₅C(═O)NR₁₆—, C₁₋₁₂hydrocarbyl group with or without substituent(s), C₁₋₁₂ cyclichydrocarbyl group with or without substituent(s), and C₁₋₁₂ heterocyclichydrocarbyl group with or without substituent(s); wherein R₁₅, R₁₆ iseach independently selected from H, C₁₋₈ hydrocarbyl group with orwithout substituent(s), C₁₋₈ cyclic hydrocarbyl group with or withoutsubstituent(s), and C₁₋₈ heterocyclic hydrocarbyl group with or withoutsubstituent(s);

X is selected from CR₁₉R₂₀, C(═O), S(═O), SO₂, and NR₂₁; wherein R₁₉,R₂₀ is each independently selected from II, cyano, hydroxyl, amino, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s), and C₁₋₈hydrocarbyloxy group with or without substituent(s); wherein R₂₁ isselected from H, C₁₋₈ hydrocarbyl group with or without substituent(s),C₁₋₈ cyclic hydrocarbyl group with or without substituent(s), and C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s);

R₁, R₈, R₁₁ is each independently selected from II, C₁₋₈ hydrocarbylgroup with or without substituent(s), C₁₋₈ cyclic hydrocarbyl group withor without substituent(s), C₁₋₈ heterocyclic hydrocarbyl group with orwithout substituent(s) and C₁₋₆ acyl group with or withoutsubstituent(s);

R₂, R₅ is each independently selected from hydrogen, OR₂₆, NR₂₇R₂₈,cyano, halogen, C₁₋₈ hydrocarbyl group with or without substituent(s),C₁₋₈ cyclic hydrocarbyl group with or without substituent(s), C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s), C₁₋₆ acylgroup with or without substituent(s) and C₁₋₆ amido group with orwithout substituent(s); wherein R₂₆, R₂₇, R₂₈ is each independentlyselected from H, C₁₋₈ hydrocarbyl group with or without substituent(s),C₁₋₈ cyclic hydrocarbyl group with or without substituent(s), and C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s);

R₃, R₆, R₇, R₉, R₁₀, R₁₂, R₁₃ is each independently selected from H,OR₂₉, NR₃₀R₃₁, cyano, halogen, nitro, C₁₋₈ hydrocarbyl group with orwithout substituent(s), cyclic hydrocarbyl group with or withoutsubstituent(s), heterocyclic hydrocarbyl group with or withoutsubstituent(s), X6S(═O)_(j)R₃₂, and X6C(═O)R₃₃; wherein j is an integerbetween 0 to 2; wherein R₂₉, R₃₀, R₃₁, R₃₂, R₃₃ is each independentlyselected from II, C₁₋₈ hydrocarbyl group with or without substituent(s),C₁₋₈ cyclic hydrocarbyl group with or without substituent(s) and C₁₋₈heterocyclic hydrocarbyl group with or without substituent(s); whereinX6 is missing or selected from O, S, and NR₃₄; wherein R₃₄ is H, C₁₋₈hydrocarbyl group with or without substituent(s), C₁₋₈ cyclichydrocarbyl group with or without substituent(s), or C₁₋₈ heterocyclichydrocarbyl group with or without substituent(s);

R₄ is selected from H, cyano, carboxyl, C₁₋₈ hydrocarbyl group with orwithout substituent(s), and C₁₋₈ hydrocarbyloxycarbonyl group with orwithout substituent(s);

a is an integer between 0 and 5;

b is an integer between 0 and 3;

c is an integer between 0 and 30;

d is an integer between 0 and 9;

e is an integer between 0 and 3;

f is an integer between 0 and 4.

In a preferred embodiment of the invention, the compound is selectedfrom the group consisting of:

Compound No. Structure of compound 3

7

10

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

The compound of the present invention may form a pharmaceuticallyacceptable salt with an inorganic acid, an organic acid or a base. Theinorganic acid includes, but is not limited to, hydrochloric acid,hydrobromic acid, nitric acid, perchloric acid, sulfuric acid,phosphoric acid and the like; the organic acid includes, but is notlimited to, methanesulfonic acid, trifluoromethanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid,lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid,propionic acid and the like; the base includes, but is not limited to,an inorganic salt and an amine.

The term of a pharmaceutically acceptable salt refers to those saltswhich, according to medical judgment, are suitable for use in contactwith human and mammalian tissues without excessive toxicity, irritation,allergic reactions, and the like. Pharmaceutically acceptable salts arewell known in the art.

The present invention also encompasses pharmaceutical compositionscontaining a prodrug of a compound of formula I. Prodrugs include suchcompounds in which the precursor molecule is covalently bonded to thefree carboxyl, hydroxyl, or amino group of the compound of formula I viaa carbonate bond, a urethane bond, an amido bond, an alkyl ester bond, aphosphate bond, or a phosphoramidate bond.

Preparation of Compound

Preparation Method

The method for preparing the compound of formula I according to thepresent invention is described in more detail below, but these specificmethods do not constitute any limitation to the present invention. Thecompound of the present invention can also be conveniently prepared bycombining various synthetic methods described in the specification orknown in the art, and such combination can be easily performed by thoseskilled in the art to which the present invention belongs.

The following reaction schemes illustrate the preparation of compoundsof the present invention. Unless otherwise indicated, A, B, W, X, Y, Z,a, b, c, d, e, f, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃in the reaction scheme and subsequent discussions are as defined above.W1 is hydroxyl, amino, or C₁₋₈ hydrocarbyl group containing a reactivesubstituent (such as hydroxyl, amino, etc.); A′ is a correspondinghalide, carboxylic acid, acyl halide, acid anhydride, ester, amide,isocyanate, sulfonyl chloride, sulfonate, sulfinyl chloride,aminosulfuryl chloride, aldehyde, ketone, α, β unsaturated carbonylcompound, etc. that can form A; Z′ is a corresponding alcohol, halide,carboxylic acid, acyl halide, acid anhydride, ester, amide, isocyanate,sulfonyl chloride, sulfonate, sulfinyl chloride, aminosulfuryl chloride,aldehyde, ketone, α, β unsaturated carbonyl compound, etc. that can form—Z—W— with W1.

In a preferred embodiment of the present invention, the method forpreparing a compound of formula I provided by the present inventionincludes the steps:

-   -   (a) reacting a compound of formula IV and a compound of formula        II in an inert solvent to obtain a compound of formula I;

wherein, each group is defined as described above.

In another preferred example, the method further includes the step of:

-   -   (b) reacting a compound of formula III and a compound of formula        V in an inert solvent to obtain a compound of formula I.

In general, compounds of formula I can be obtained from those of formulaIII as described in the following schemes:

In compound II, when W is an ether, it can be prepared by directlynucleophilic substitution of formula III (W1=OH) with an intermediatecontaining a leaving group under the action of a base, or by aphoto-extension reaction with an alcohol; when W is an ester orcarbamate (NHCO₂), it can be prepared by reacting formula III (W1=OH)with an acyl chloride, an activated ester (amide), a carboxylic acid, oran isocyanate under the action of a base; when W is an amine, it can beprepared by directly nucleophilic substitution of formula III (W1=NH₂)with an intermediate containing a leaving group under the action of abase, or by reductive amination reaction of formula III (W1=NH₂) with analdehyde/ketone; when W it is an amide, alkoxycarbonylamine (OCONH) orurea, it can be prepared by reacting formula III (W1=NH₂) with thecorresponding acyl chloride, activated ester (amide), carboxylic acidand isocyanate under the action of a base.

In compound I, when A and a nitrogen atom are connected through a C—Nbond, it can be prepared by direct substitution reaction or reductiveamination reaction; when A and a nitrogen atom are connected in the formof amide, urea, carbamate, sulfonamide, or sulfamide, it can be preparedby using the corresponding acyl chloride, activated ester (amide),carboxylic acid, isocyanate, sulfonyl chloride, or sulfuryl chloride.

Generally, according to the connection structure of A and W, compound Ican also be obtained by first connecting formula IV to the middle chainand then reacting with formula III. The chemical synthesis method usedis the same as described above.

Compounds of formula III or IV can be obtained by known syntheticmethods or can be easily obtained commercially.

Use of Compounds of Formula I

The compounds of formula I can be used for one or more of the followingpurposes:

(a) preparation of drugs for the treatment of diseases related to theactivity or expression level of anaplastic lymphoma kinase (ALK);

(b) preparation of anaplastic lymphoma kinase (ALK) targeted inhibitorsor degradation agents;

(c) non-therapeutic inhibition or degradation of anaplastic lymphomakinase (ALK) in vitro;

(d) non-therapeutic inhibition of tumor cell proliferation in vitro;and/or

(e) treatment of diseases related to the activity or expression level ofanaplastic lymphoma kinase (ALK).

In another preferred example, the disease related to the activity orexpression level of anaplastic lymphoma kinase (ALK) is a tumor,preferably the tumor is selected from the group consisting of non-smallcell lung cancer, inflammatory myofibroblastoma etc. . . . .

The compound of formula I of the present invention can be used toprepare a pharmaceutical composition, which comprises: (i) an effectiveamount of a compound of formula I, or a pharmaceutically acceptable saltthereof; and (ii) a pharmaceutically acceptable carrier.

In another preferred example, the effective amount refers to atherapeutically effective amount or an inhibitory effective amount.

The compound of formula I of the present invention can also be used in amethod for inhibiting or degrading anaplastic lymphoma kinase (ALK), andthe inhibition is a non-therapeutic inhibition in vitro or a therapeuticinhibition.

In another preferred example, when an inhibitory effective amount of thecompound of formula I of the present invention or a pharmaceuticallyacceptable salt thereof is administered to an inhibitory subject, theinhibitory effective amount is 0.001-500 nmol/L, preferably 0.01-200nmol/L.

In particular, the present invention also provides a method of treatinga disease related to the activity or expression level of anaplasticlymphoma kinase (ALK), and the method comprises: administering atherapeutically effective amount of a compound of formula I or apharmaceutical composition containing the compound of formula I as anactive ingredient to a subject in need of treatment.

Pharmaceutical Composition and Administration

Since the compound of the present invention has excellent inhibitoryactivity on anaplastic lymphoma kinase (ALK), the compound of thepresent invention and its various crystal forms, pharmaceuticallyacceptable inorganic or organic salts, hydrates or solvates and thepharmaceutical composition containing the compound of the presentinvention as a main active ingredient can be used for treating,preventing, and alleviating diseases related to Alk activity orexpression level. According to the prior art, the compounds of thepresent invention are useful for treating diseases including tumors andthe like.

The pharmaceutical composition of the present invention comprises thecompound of the present invention or the pharmaceutically acceptablesalt thereof in a safe and effective amount range and pharmaceuticallyacceptable excipients or carriers. The “safe and effective amount”means: the amount of the compound is sufficient to significantly improvethe condition, but will not have serious side effects. Generally, thepharmaceutical composition contains 1-2000 mg of the compound of thepresent invention per dose, preferably, 5-200 mg the compound of thepresent invention per dose. Preferably, “one dose” is a capsule ortablet.

“Pharmaceutically acceptable carrier” means one or more compatible solidor liquid fillers or gelatinous materials which are suitable for humanuse and should be of sufficient purity and sufficiently low toxicity.“Compatible” herein means that each component in the composition can bewell blended with a compound of the present invention and with eachother between them, without significantly reducing the efficacy of thecompounds. Some examples of pharmaceutically acceptable carriers includecellulose and the derivatives thereof (such as sodium carboxymethylcellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin,talc, solid lubricants (such as stearic acid, magnesium stearate),calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanutoil, olive oil, etc.), polyols (such as propylene glycol, glycerol,mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agent(such as sodium dodecyl sulfate), coloring agents, flavoring agents,stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

There is no special limitation of administration mode for the compoundor pharmaceutical compositions of the present invention, and therepresentative administration mode includes (but is not limited to):oral, intratumoral, rectal, parenteral (intravenous, intramuscular orsubcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In these solid dosage forms, the activecompounds are mixed with at least one conventional inert excipient (orcarrier), such as sodium citrate or dicalcium phosphate, or mixed withany of the following components: (a) fillers or compatibilizer, forexample, starch, lactose, sucrose, glucose, mannitol and silicic acid;(b) binders, for example, hydroxymethyl cellulose, alginates, gelatin,polyvinylpyrrolidone, sucrose and arabic gum; (c) humectant, such as,glycerol; (d) disintegrating agents such as agar, calcium carbonate,potato starch or tapioca starch, alginic acid, certain compositesilicates, and sodium carbonate; (e) dissolution-retarding agents, suchas paraffin; (f) absorption accelerators, for example, quaternaryammonium compounds; (g) wetting agents, such as cetyl alcohol andglyceryl monostearate; (h) adsorbents, for example, kaolin; and (i)lubricants such as talc, stearin calcium, magnesium stearate, solidpolyethylene glycol, sodium lauryl sulfate, or the mixtures thereof. Incapsules, tablets and pills, the dosage forms may also contain bufferingagents.

The solid dosage forms, such as tablets, sugar pills, capsules, pillsand granules, can be prepared by using coating and shell materials, suchas enteric coatings and any other materials known in the art. They cancontain an opaque agent and the release of the active compounds orcompounds in the compositions can be released in a delayed mode in agiven portion of the digestive tract. Examples of the embeddingcomponents include polymers and waxes. If necessary, the activecompounds and one or more above excipients can form microcapsules.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups or tinctures. Inaddition to the active compounds, the liquid dosage forms may containany conventional inert diluents known in the art such as water or othersolvents, solubilizers and emulsifiers, for example, ethanol,isopropanol, ethyl carbonate, ethyl acetate, propylene glycol,1,3-butanediol, dimethyl formamide, as well as oil, in particular,cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil andsesame oil, or the combination thereof.

Besides these inert diluents, the composition may also contain additivessuch as wetting agents, emulsifiers and suspending agent, sweetener,flavoring agents and perfume.

In addition to the active compounds, the suspension may containsuspending agent, for example, ethoxylated isooctadecanol,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, methanol aluminum and agar, or the combination thereof.

The compositions for parenteral injection may comprise physiologicallyacceptable sterile aqueous or anhydrous solutions, dispersions,suspensions or emulsions, and sterile powders which can be re-dissolvedinto sterile injectable solutions or dispersions. Suitable aqueous andnon-aqueous carriers, diluents, solvents or excipients include water,ethanol, polyols and any suitable mixtures thereof.

The dosage forms for topical administration of compounds of the presentinvention include ointments, powders, patches, aerosol, and inhalants.The active ingredients are mixed with physiologically acceptablecarriers and any preservatives, buffers, or propellant if necessary,under sterile conditions.

Compounds of the present invention can be administrated alone, or incombination with any other pharmaceutically acceptable compounds.

When the pharmaceutical compositions are used, a safe and effectiveamount of compound of the present invention is applied to a mammal (suchas human) in need of, in which the dose of administration is apharmaceutically effective dose. For a person weighed 60 kg, the dailydose is usually 1-2000 mg, preferably 5-500 mg. Of course, theparticular dose should also depend on various factors, such as the routeof administration, the healthy condition of patient, which are wellwithin the skills of an experienced physician.

The main advantages of the invention include:

1. compounds of formula I are provided.

2. a novel ALK inhibitor and degradation agent, the preparation thereofand the application thereof are provided. The inhibitor and degradationagent can inhibit the activity of ALK and degrade ALK at very lowconcentrations.

3. a pharmaceutical composition for treating diseases related to ALKactivity is provided.

The present invention will be further illustrated below with referenceto the specific examples. It should be understood that these examplesare only to illustrate the invention but not to limit the disclosure ofthe invention. The experimental methods without specific conditions inthe following embodiments are generally carried out according toconventional conditions, or in accordance with the conditionsrecommended by the manufacturer. The biological materials involved inthe embodiments of the present invention can be obtained fromcommercially available channels, unless otherwise specified. Unlessstated otherwise, percentages and parts are percentages by weight andparts by weight.

Example 1 Preparation of Compound (3)

Step 1:

2.14 g of 6-bromohexanoyl chloride and 1.37 g of pomalidomide weredissolved in 50 ml of THF (tetrahydrofuran), and the mixture was stirredat reflux for 8 h. Then the solvent was removed under reduced pressureand the residue was purified by column chromatography to obtain 1.22 gof compound (1). MS (ESI): 450 [M+H]⁺.

Step 2:

250 mg of compound (1), 365 mg of compound (2) and 650 mg ofdiisopropylethylamine were dissolved in 5 ml of N, N-dimethylformamide.The mixture was stirred at 80° C. for 6 h, and then cooled to roomtemperature. After concentration, the residue was purified by columnchromatography to obtain 350 mg of compound (3) with a yield of 68.0%.MS (ESI): 927 [M+H]⁺. ¹H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 8.28 (d,J=8.4 Hz, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.95 (dd, J=8.0, 1.6 Hz, 1H),7.87 (d, J=7.2 Hz, 1H), 7.79 (dd, J=8.4, 7.6 Hz, 1H), 7.62 (m, 1H), 7.60(s, 1H), 7.25 (m, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.82 (s, 1H), 6.52 (t,J=5.6 Hz, 1H), 4.89 (dd, J=11.6, 4.8 Hz, 1H), 4.48 (m, 1H), 3.25 (m,1H), 2.66-2.91 (m, 6H), 2.52 (t, J=7.2 Hz, 2H), 2.11 (s, 3H), 2.10-2.45(m, 6H), 1.71-1.90 (m, 4H), 1.40-1.65 (m, 6H), 1.34 (d, J=5.6 Hz, 6H),1.31 (d, J=7.2 Hz, 6H).

Example 2 Preparation of Compound (7)

Step 1:

100 mg of 4-hydroxythalidomide, 96 mg of triethylene glycol monobenzylether, and 100 mg of triphenylphosphine were dissolved in 10 ml ofanhydrous THF, and then 95 mg of DIAD (diisopropyl azodicarboxylate) wasadded dropwise. The reaction was carried out at room temperature for 2h. THF was removed under reduced pressure, and 110 mg of compound (4)was obtained after purification by column chromatography. MS (ESI): 497[M+H]⁺.

Step 2:

100 mg of compound (4) and 100 mg of 10% Pd—C were added into 10 ml ofmethanol and the mixture was hydrogenated at room temperature overnight.Then the mixture was filtered and the filtrate was concentrated. Theresidue was purified by column chromatography to obtain 40 mg ofcompound (5). MS (ESI): 407 [M+H]⁺.

Step 3:

30 mg of compound (5) was dissolved in 5 ml of dichloromethane, then 47mg of Dess-martin oxidant was added. The mixture was reacted at roomtemperature for 3 h. To the reaction system were added a saturatedaqueous solution of NaHCO₃ and a saturated aqueous solution of Na₂S₂O₃,and stirred for 5 min. The organic layer was separated, dried overanhydrous Na₂S₂O₃, and concentrated to dryness. The obtained compound(6) was directly used in the next step.

After compound (6) was dissolved in 7 ml of dichloromethane, 45 mg ofraw material (2) and 23 mg of NaBH(OAc)₃ were added, and the mixture wasreacted overnight at room temperature. Dichloromethane was distilled offunder reduced pressure. 37 mg of compound (7) was obtained afterpurification by column chromatography. 946 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 9.49 (s, 1H), 8.58 (d, J=8.5 Hz, 1H), 8.15 (s, 1H), 7.98 (s,1H), 7.92 (d, J=7.5 Hz, 1H), 7.60-7.69 (m, 2H), 7.56 (s, 1H), 7.47 (d,J=7.5 Hz, 1H), 7.24-7.27 (m, 2H), 6.81 (s, 1H), 4.93 (dd, J=12.0, 5.0Hz, 1H), 4.53 (m, 1H), 4.35 (t, J=4.2 Hz, 2H), 3.95 (t, J=4.8 Hz, 2H),3.81 (m, 2H), 3.70 (br, 2H), 3.67 (m, 2H), 3.26 (m, 1H), 3.18 (br, 2H),2.65-2.90(m, 61-I), 2.11 (s, 3H), 2.10-2.32 (m, 4H), 1.70-1.91 (m, 4H),1.35 (d, J=5.5 Hz, 6H), 1.32 (d, J=7.0 Hz, 6H).

Example 3 Preparation of Compound (10)

Step 1:

174 mg of benzyl 2-(2-(2-bromoethoxy)ethoxy)acetate, 100 mg of potassiumcarbonate, 20 mg of potassium iodide and 100 mg of pomalidomide wereadded into 20 ml of DMF (N, N-dimethylformamide), and reacted at 80° C.overnight. The reaction solution was purified by column chromatographyto obtain 113 mg of compound (8). MS (ESI): 510 [M+H]⁺.

Step 2:

100 mg of compound (8) and 100 mg of 10% Pd—C were added into 10 ml ofmethanol and the mixture was hydrogenated at room temperature overnight.Then the mixture was filtered and the filtrate was concentrated. Theresidue was purified by column chromatography to obtain 73 mg ofcompound (9). MS (ESI anion): 418 [M−H]⁻.

Step 3:

50 mg of compound (9) and 50 mg of raw material (2) were dissolved in 5ml of dichloromethane, and 20 mg of HOBt (1-hydroxybenzotriazole) and 40mg of EDC (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride)were added. The mixture was reacted at room temperature overnight.Dichloromethane was distilled off under reduced pressure, and 45 mg ofcompound (10) was obtained after purification by column chromatography.¹H NMR (400 MHz, CDCl₃) δ 9.49 (s, 1H), 8.58 (d, J=8.4 Hz, 1H), 8.15(s,1H), 7.98 (s, 1H), 7.98 (s, 1H), 7.92 (dd, J=8.0, 1.6 Hz, 1H), 7.62 (m,1H), 7.56 (s, 1H), 7.49 (dd, J=8.4, 7.6 Hz, 1H), 7.25 (m, 1H), 7.11 (d,J=7.2 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.82 (s, 1H), 6.52 (t, J=5.6 Hz,1H), 4.90 (dd, J=12.0, 5.6 Hz, 1H), 4.67 (s, 2H), 4.54 (m, 1H), 3.73 (m,4H), 3.47 (m, 2H), 3.26 (m, 1H), 3.19 (br, 2H), 2.63-2.89 (m, 6H), 2.14(s, 3H), 2.08-2.30 (m, 3H), 1.71-1.92 (m, 4H), 1.35 (d, J=6.0 Hz, 6H),1.32 (d, J=6.8 Hz, 6H).

Example 4 Preparation of Compound (13)

Step 1:

200 mg of raw material (2) was dissolved in 10 ml of dichloromethane,100 mg of triethylamine and 200 mg of 5-benzyloxypentanesulfonylchloride were added, and the mixture was reacted at room temperatureovernight. The dichloromethane was distilled off under reduced pressureand 267 mg of compound (11) was obtained after purification by columnchromatography. MS (ESI): 798

[M+H]⁺.

Step 2:

200 mg of compound (11) was added into 20 ml of methanol and 200 mg of10% Pd—C, the gas was changed 3 times with H₂, and the mixture wasreacted at room temperature overnight. Then the mixture was filtered andthe filtrate was concentrated. The residue was purified by columnchromatography to obtain 154 mg of compound (12). MS (ESI): 708 [M+H]⁺.

Step 3:

100 mg of 4-hydroxythalidomide, 100 mg of triphenylphosphine and 150 mgof compound (12) were dissolved in 30 ml of anhydrous tetrahydrofuran,100 mg of DIAD (diisopropyl azodicarboxylate) was added dropwise, andthe reaction was carried out at room temperature for 3 h.Tetrahydrofuran was removed under reduced pressure, and 75 mg ofcompound (13) was obtained after purification by column chromatography.MS (ESI): 964 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.48 (s, 1H), 8.58(d,J=8.4 Hz, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.92 (d, J=7.5 Hz, 1H),7.60-7.69 (m, 2H), 7.56 (s, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.24-7.27 (m,1H), 6.81 (s, 1H), 4.90(dd, J=12.0, 4.4 Hz, 1H), 4.48(m, 1H), 3.55(t,J=7.2 Hz, 2H), 3.25-3.34(m, 3H), 2.66-2.91(m, 5H), 2.11 (s, 3H),2.10-2.46 (m, 4H), 1.71-1.90 (m, 4H), 1.40-1.65 (m, 6H), 1.35 (d, J=5.6Hz, 6H), 1.31 (d, J=7.2 Hz, 6H).

Similarly, the following compounds were prepared by a method similar tothe above example:

Refe ence example Com- for syn- pound thesis No. Structure of compoundmethod MS(ESI) 114

2, 3 989[M + H]⁺ 115

2 990[M + H]⁺ 16

1 913[M + H]⁺ 17

1 899[M + H]⁺ 18

1 885[M + H]⁺ 19

1 973[M + H]⁺ 20

1 1017[M + H]⁺  21

2 902[M + H]⁺ 22

2 900[M + H]⁺ 23

2 886[M + H]⁺ 24

2 872[M + H]⁺ 25

2 1034[M + H]⁺  26

2 1078[M + H]⁺  27

2, 3 901[M + H]⁺ 28

2, 3 899[M + H]⁺ 29

2, 3 885[M + H]⁺ 30

2, 3 871[M + H]⁺ 31

2, 3 1033[M + H]⁺  32

2, 3 1077[M + H]⁺  33

2, 3 914[M + H]⁺ 34

2, 3 958[M + H]⁺ 35

2, 3 1002[M + H]⁺  36

2, 3 1046[M + H]⁺  37

2, 3 1090[M + H]⁺  38

2, 3 1134[M + H]⁺  39

2 915[M + H]⁺ 40

2 959[M + H]⁺ 41

2 1003[M + H]⁺  42

2 1047[M + H]⁺  43

2 1091[M + H]⁺  44

2 1135[M + H]⁺  45

2, 3 945[M + H]⁺

Example 5 Testing the ALK Inhibition Activity of Compound by CaliperAssay

The experimental steps were as follows:

Preparation of 1×kinase reaction buffer (50 mM HEPES, PH 7.5; 0.0015%Brij-35) and kinase reaction termination solution (100 mM HEPES, PH 7.5;0.0015% Brij-35; 0.2% Coating Reagent; 50 mM EDTA);

Preparation of experimental samples: 100 μl of 5 μM sample solution(dissolved in 100% DMSO) was added to a 96-well plate to obtain a50×sample solution. As controls, two wells containing only 100 μL of100% DMSO were set on the same plate. One was served as a controlwithout samples and the other was served as a control without enzymes.10 μL of sample and 90 μL, of 1×kinase reaction buffer were added to a96-well plate as a transfer plate. The transfer plate was shaken for 10minutes.

Preparation of the test plate: taking 5 μL of each of the preparedsamples from the 96-well transfer plate into a 384-well plate.

Kinase reaction: to 5 μL of 5×compound solution (dissolved in DMSO,diluted 10 times with water) was added 10 μL of 2.5×ALK kinase solution(kinase was diluted with 1×kinase reaction buffer), which was incubatedat room temperature for 10 min, and then 10 μL of 2.5×substrate peptidesolution (FAM-labeled peptide and ATP were diluted with 1×kinasereaction buffer) was added.

Termination of the kinase reaction: 25 μL of kinase reaction terminationsolution was added after being reacted at 28° C. for a period of time.

The fluorescence (F) was tested on a Caliper and data was collected.

The inhibition rate of kinase activity was calculated: the percentinhibition rate of kinaseactivity=(F_(DMSO control)−F_(sample))/(F_(DMSO control)−F_(negative control))×100,with DMSO as the solution control, and no kinase as the negativecontrol.

The results show that the inhibitory activity of compound (100 nM) onALK is shown in the following table:

Compound No. Inhibition(%) 3 98% 7 97% 10 99% 13 69% 14 89% 15 95% 4598%

Example 6 Testing the ALK Protein Degradation Activity of Compound byWestern Blot

Cell lines: H2228 cell lines (human non-small cell line lung cancercells, available from ATCC) were cultured in RPMI1640 medium containing10% calf serum in a 37° C., 5% CO₂, and saturated humidity incubator.

DMSO control group and compound intervention group (10 μM) were set.Cells were collected after the treatment for 24 hours, then 100 μL ofpre-chilled cell lysate was added and cells were lysed on ice for 30minutes. Total cell protein was extracted, and protein concentration wasdetermined and quantified by diquinolinecarboxylic acid (BCA) method.After routine gelatinization, loading, electrophoresis, thentransferring to membrane and blocking, mouse anti-human ALK (1:1000) wasadded respectively, and incubated at 4° C. overnight. The mixture wasrinsed and then horseradish peroxidase labeled goat anti-rabbit IgG(1:5000) was added. After the rinsing it was developed by the ECLdeveloping solution, the Bio-Rad gel imaging system was used forscanning and imaging, and the computer software was used for analysis.Glycerol phosphate dehydrogenase (GAPDH) was used as an internalcontrol.

Image J software was used to analyze the gray scale of each band tocalculate the degradation rate of the compound to degrade ALK protein.

The results show that the degradation activity of the compound (1 μM) onALK protein in 112228 cells is shown in the following table:

ALK degradation Compound No. activity 3 ++++ 7 ++++ 10 ++++ 13 ++++ 14++++ 15 ++++ 16 ++++ 17 ++++ 18 ++++ 19 ++++ 20 ++++ 21 +++ 22 +++ 23+++ 24 +++ 25 ++++ 26 +++ 27 ++++ 28 ++++ 29 +++ 30 +++ 31 ++++ 32 +++33 ++++ 34 ++++ 35 ++++ 36 ++++ 37 +++ 38 +++ 39 ++++ 40 ++++ 41 ++++ 42++++ 43 +++ 44 +++ 45 ++++ Note: In the above table, “−” represents nodegradation activity, “+” represents a degradation rate of 10%-30%, “++”represents a degradation rate of 30%-50%, and “+++” represents adegradation rate of 50%-90%, and “++++” means the degradation rate isgreater than 90%.

Example 7 Testing the Inhibitory Effect of Formula Compound on theProliferation of SU-DHL-1 Cells by CTG Assay

The inhibitory effect of the compound on the proliferation of SU-DHL-1cells (B lymphoma cells) was determined by the CCK8 method in vitro. TheCells were cultured and the compound was prepared referring to themethod of Example 7, and the culture time after administration was 72hours. Subsequently, an appropriate amount of CTG reagent was added, theluminescence value was measured, and the inhibition rate was calculated.

The inhibitory effect of the synthesized compound (100 μM) on theproliferation of SU-DHL-1 cells in vitro is shown in the table below:

Compound No. Inhibition(%) 3 72 7 98 14 99 15 100 45 97

The above result shows that the synthesized compounds of formula I havegood inhibitory activity on the proliferation of SU-DHL-1 cells.

All publications mentioned herein are incorporated by reference as ifeach individual document is cited as a reference, as in the presentapplication. It should also be understood that, after reading the aboveteachings of the present invention, those skilled in the art can makevarious changes or modifications, equivalents of which falls in thescope of claims as defined in the appended claims.

What is claimed:
 1. A compound represented by the following formula I,or a pharmaceutically acceptable salt thereof:

wherein — is a single bond;

is a single or a double bond; A is missing a bond, C(═O)X1, orsubstituted or unsubstituted C₁₋₈ hydrocarbyl group, wherein X1 is abond or (CR₃₅R₃₆)_(k)O, wherein R₃₅ and R₃₆ are each independentlyselected from the group consisting of H and substituted or unsubstitutedC₁₋₈ hydrocarbyl group, and k is an integer between 0 and 3; W is abond, O, or NR₁₇, wherein R₁₇ is H or substituted or unsubstituted C₁₋₈hydrocarbyl group; Y is (CR₂₂R₂₃)_(h), wherein h is an integer between 0and 30, and R₂₂ and R₂₃ are each independently selected from the groupconsisting of H, cyano, hydroxyl, amino, and substituted andunsubstituted C₁₋₈ hydrocarbyl group; Z is (CR₂₄R₂₅)_(i), wherein i isan integer between 0 and 30, and R₂₄ and R₂₅ are each independentlyselected from the group consisting of H, cyano, hydroxyl, amino, andsubstituted or unsubstituted C₁₋₈ hydrocarbyl group; B is O; X is CH₂;or C(═O); R₁ is selected from the group consisting of H, substituted orunsubstituted C₁₋₈ hydrocarbyl group, substituted or unsubstituted C₁₋₈cyclic hydrocarbyl group, substituted or unsubstituted C₁₋₈ heterocyclichydrocarbyl group, and substituted or unsubstituted C₁₋₆ acyl group; R₈is selected from the group consisting of H, substituted or unsubstitutedC₁₋₈ hydrocarbyl group, substituted or unsubstituted C₁₋₈ cyclichydrocarbyl group, substituted or unsubstituted C₁₋₈ heterocyclichydrocarbyl group, and substituted or unsubstituted C₁₋₆ acyl group; R₁₁is selected from the group consisting of H, substituted or unsubstitutedC₁₋₈ hydrocarbyl group, substituted or unsubstituted C₁₋₈ cyclichydrocarbyl group, substituted or unsubstituted C₁₋₈ heterocyclichydrocarbyl group and substituted or unsubstituted C₁₋₆ acyl group; R₂is selected from the group consisting of hydrogen, OR₂₆, NR₂₇R₂₈, cyano,halogen, substituted or unsubstituted C₁₋₈ hydrocarbyl group,substituted or unsubstituted C₁₋₈ cyclic hydrocarbyl group, substitutedor unsubstituted C₁₋₈ heterocyclic hydrocarbyl group, substituted orunsubstituted C₁₋₆ acyl group, and substituted or unsubstituted C₁₋₆amido group, wherein R₂₆, R₂₇, and R₂₈ are each independently selectedfrom the group consisting of H and substituted or unsubstituted C₁₋₈hydrocarbyl group; R₅ is selected from the group consisting of hydrogen,OR₂₆, NR₂₇R₂₈, cyano, halogen, substituted or unsubstituted C₁₋₈hydrocarbyl group, substituted or unsubstituted C₁₋₈ cyclic hydrocarbylgroup, substituted or unsubstituted C₁₋₈ heterocyclic hydrocarbyl group,substituted or unsubstituted C₁₋₆ acyl group, and substituted orunsubstituted C₁₋₆ amido group, wherein R₂₆, R₂₇, and R₂₈ are eachindependently selected from the group consisting of H and substituted orunsubstituted C₁₋₈ hydrocarbyl group; R₃ is selected from the groupconsisting of H, OR₂₉, NR₃₀R₃₁, cyano, halogen, nitro, substituted orunsubstituted C₁₋₈ hydrocarbyl group, substituted or unsubstitutedcyclic hydrocarbyl group, and substituted or unsubstituted heterocyclichydrocarbyl group, wherein R₂₉, R₃₀, and R₃₁ are each independentlyselected from the group consisting of H and substituted or unsubstitutedC₁₋₈ hydrocarbyl group; R₆ is selected from the group consisting of H,OR₂₉, NR₃₀R₃₁, cyano, halogen, nitro, substituted or unsubstituted C₁₋₈hydrocarbyl group, substituted or unsubstituted cyclic hydrocarbylgroup, and substituted or unsubstituted heterocyclic hydrocarbyl group;wherein R₂₉, R₃₀, and R₃₁ are each independently selected from the groupconsisting of H and substituted or unsubstituted C₁₋₈ hydrocarbyl group;R₇ is selected from the group consisting of H, OR₂₉, NR₃₀R₃₁, cyano,halogen, nitro, substituted or unsubstituted C₁₋₈ hydrocarbyl group,substituted or unsubstituted cyclic hydrocarbyl group, and substitutedor unsubstituted heterocyclic hydrocarbyl group, wherein R₂₉, R₃₀, andR₃₁ are each independently selected from the group consisting of H andsubstituted or unsubstituted C₁₋₈ hydrocarbyl group; R₉ is selected fromthe group consisting of H, OR₂₉, NR₃₀R₃₁, cyano, halogen, nitro,substituted or unsubstituted C₁₋₈ hydrocarbyl group, substituted orunsubstituted cyclic hydrocarbyl group, and substituted or unsubstitutedheterocyclic hydrocarbyl group, wherein R₂₉, R₃₀, and R₃₁ are eachindependently selected from the group consisting of H and substituted orunsubstituted C₁₋₈ hydrocarbyl group; R₁₀ is selected from the groupconsisting of H, OR₂₉, NR₃₀R₃₁, cyano, halogen, nitro, substituted orunsubstituted C₁₋₈ hydrocarbyl group, substituted or unsubstitutedcyclic hydrocarbyl group, and substituted or unsubstituted heterocyclichydrocarbyl group, wherein R₂₉, R₃₀, and R₃₁ are each independentlyselected from the group consisting of H and substituted or unsubstitutedC₁₋₈ hydrocarbyl group; R₁₂ is selected from the group consisting of H,OR₂₉, NR₃₀R₃₁, cyano, halogen, nitro, substituted or unsubstituted C₁₋₈hydrocarbyl group, substituted or unsubstituted cyclic hydrocarbylgroup, substituted or unsubstituted heterocyclic hydrocarbyl group,X6S(═O)_(j)R₃₂, and X6C(═O)R₃₃, wherein j is an integer between 0 to 2,R₂₉, R₃₀, R₃₁, R₃₂, and R₃₃ are each independently selected from thegroup consisting of H and substituted or unsubstituted C₁₋₈ hydrocarbylgroup, and X6 is a bond; R₁₃ is selected from the group consisting of H,OR₂₉, NR₃₀R₃₁, cyano, halogen, nitro, substituted or unsubstituted C₁₋₈hydrocarbyl group, substituted or unsubstituted cyclic hydrocarbylgroup, and substituted or unsubstituted heterocyclic hydrocarbyl group,wherein R₂₉, R₃₀, and R₃₁ are each independently selected from the groupconsisting of H and substituted or unsubstituted C₁₋₈ hydrocarbyl group;R₄ is selected from the group consisting of H, cyano, carboxyl,substituted or unsubstituted C₁₋₈ hydrocarbyl group, and substituted orunsubstituted C₁₋₈ hydrocarbyloxycarbonyl group; a is an integer between0 and 5; b is an integer between 0 and 3; c is an integer between 1 and30; d is an integer between 0 and 9; e is an integer between 0 and 3; fis an integer between 0 and 4; and wherein any of the substituents isselected from the group consisting of halogen, unsubstituted orhalogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkoxy,unsubstituted or halogenated C2-C6 alkoxyalkyl, unsubstituted orhalogenated C3-C8 cycloalkyl, unsubstituted or halogenated C2-C6alkylcarbonyl, unsubstituted or halogenated C1-C6 alkylene-hydroxyl, andunsubstituted or C1-C6 alkyl substituted amine.
 2. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein: in formula I, A is a bond; W is a bond or O; Y is(CR₂₂R₂₃)_(h), wherein R₂₂ and R₂₃ are each independently selected fromthe group consisting of H, hydroxyl, and substituted or unsubstitutedC₁₋₄ hydrocarbyl group, and h is an integer between 0 and 3; Z is(CR₂₄R₂₅)_(i), wherein R₂₄ and R₂₅ are each independently selected fromthe group consisting of H, hydroxyl, and substituted or unsubstitutedC₁₋₄ hydrocarbyl group and i is an integer between 0 and 3; and c is aninteger between 1 and 6; or in formula I, A is a bond; W is NR₁₇,wherein R₁₇ is H or substituted or unsubstituted C₁₋₄ hydrocarbyl group;Y is (CR₂₂R₂₃)_(h), wherein R₂₂ and R₂₃ are each independently selectedfrom the group consisting of H, hydroxyl, and substituted orunsubstituted C₁₋₄ hydrocarbyl group, and h is an integer between 0 and3; Z is (CR₂₄R₂₅)_(i), wherein R₂₄ and R₂₅ are each independentlyselected from the group consisting of H, hydroxyl, and substituted orunsubstituted and C₁₋₄ hydrocarbyl group, and i is an integer between 0and 4; and c is an integer between 1 and 6; or in formula I, A is abond; W is a bond; Y is (CR₂₂R₂₃)_(h), wherein R₂₂ and R₂₃ are eachindependently selected from the group consisting of H, hydroxyl, andsubstituted and unsubstituted C₁₋₄ hydrocarbyl group, and h is aninteger between 0 and 3; Z is (CR₂₄R₂₅)_(i), wherein R₂₄, and R₂₅ areeach independently selected from the group consisting of H, hydroxyl,and substituted or unsubstituted C₁₋₄ hydrocarbyl group, and i is aninteger between 0 and 3; and c is an integer between 1 and
 10. 3. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein in formula I, X is C(═O).
 4. The compound according toclaim 1, or a pharmaceutically acceptable salt thereof, wherein R₁₂ isselected from the group consisting of hydrogen, halogen, cyano, nitro,and X6S(═O)_(j)R₃₂, wherein j is 2, and R₃₂ is selected from the groupconsisting of H and substituted or unsubstituted C₁₋₆ alkyl.
 5. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein R₄ is selected from the group consisting of H, cyano,and substituted or unsubstituted C₁₋₆ alkyl.
 6. The compound accordingto claim 1, or a pharmaceutically acceptable salt thereof, wherein thecompound is selected from: Com- pound No. Structure of compound 7

10

14

15


7. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein the compound is represented by formula I′:


8. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein the compound is represented by formula I″:


9. A pharmaceutical composition, wherein the composition comprises thecompound according to claim h or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.